Wideband finely tunable, ultralow-phase noise microwave generation in a Brillouin cavity.

A novel, to the best of our knowledge, approach to generate frequency-tunable microwave sources with low-phase-noise based on a Brillouin laser frequency comb is proposed and experimentally demonstrated. The Brillouin laser frequency comb is generated by combining stimulated Brillouin scattering, frequency shifting optical injection locking, modulation sideband optical injection locking (MSOIL), and four-wave mixing effects. By beating the generated comb lines, the microwave is generated with an extremely low-level phase noise of -120 dBc/Hz at a 10-kHz offset. The frequency of the microwave signal can be finely tuned in steps of a Brillouin cavity mode spacing (i.e., 2 MHz) and coarsely adjusted to integer times the applied RF signal frequency in the MSOIL unit. Remarkably, the phase noise of the microwave source can be kept at almost the same low level during the whole tuning process over the frequency range of 30-75 GHz. The proposed tunable low-phase-noise microwave generation approach has great potential applications in communications, radars, and metrology.

Melt-electrowriting-enabled anisotropic scaffolds loaded with valve interstitial cells for heart valve tissue Engineering.

Tissue engineered heart valves (TEHVs) demonstrates the potential for tissue growth and remodel, offering particular benefit for pediatric patients. A significant challenge in designing functional TEHV lies in replicating the anisotropic mechanical properties of native valve leaflets. To establish a biomimetic TEHV model, we employed melt-electrowriting (MEW) technology to fabricate an anisotropic PCL scaffold. By integrating the anisotropic MEW-PCL scaffold with bioactive hydrogels (GelMA/ChsMA), we successfully crafted an elastic scaffold with tunable mechanical properties closely mirroring the structure and mechanical characteristics of natural heart valves. This scaffold not only supports the growth of valvular interstitial cells (VICs) within a 3D culture but also fosters the remodeling of extracellular matrix of VICs. The in vitro experiments demonstrated that the introduction of ChsMA improved the hemocompatibility and endothelialization of TEHV scaffold. The in vivo experiments revealed that, compared to their non-hydrogel counterparts, the PCL-GelMA/ChsMA scaffold, when implanted into SD rats, significantly suppressed immune reactions and calcification. In comparison with the PCL scaffold, the PCL-GelMA/ChsMA scaffold exhibited higher bioactivity and superior biocompatibility. The amalgamation of MEW technology and biomimetic design approaches provides a new paradigm for manufacturing scaffolds with highly controllable microstructures, biocompatibility, and anisotropic mechanical properties required for the fabrication of TEHVs.

A bibliometric analysis of interstitial cells of Cajal research.

Objective: The significance of interstitial cells of Cajal (ICC) in the gastrointestinal tract has garnered increasing attention. In recent years, approximately 80 articles on ICC have been published annually in various journals. However, no bibliometric study has specifically focused on the literature related to ICC. Therefore, we conducted a comprehensive bibliometric analysis of ICC to reveal dynamic scientific developments, assisting researchers in exploring hotspots and emerging trends while gaining a global perspective. Methods: We conducted a literature search in the Web of Science Core Collection (WoSCC) from January 1, 2013, to December 31, 2023, to identify relevant literature on ICC. We employed bibliometric software, namely VOSviewer and CiteSpace, to analyze various aspects including annual publication output, collaborations, research hotspots, current status, and development trends in this domain. Results: A total of 891 English papers were published in 359 journals by 928 institutions from 57 countries/regions. According to the keyword analysis of the literature, researchers mainly focused on "c-Kit," "expression," "smooth muscle," and "nitric oxide" related to ICC over the past 11 years. However, with "SIP syncytium," "ANO1," "enteric neurons," "gastrointestinal stromal tumors (GIST)," and "functional dyspepsia (FD)," there has been a growing interest in the relationship between ANO1, SIP syncytium, and ICC, as well as the role of ICC in the treatment of GIST and FD. Conclusion: Bibliometric analysis has revealed the current status of ICC research. The association between ANO1, SIP syncytium, enteric neurons and ICC, as well as the role of ICC in the treatment of GIST versus FD has become the focus of current research. However, further research and collaboration on a global scale are still needed. Our analysis is particularly valuable to researchers in gastroenterology, oncology, and cell biology, providing insights that can guide future research directions.

Highly efficient degradation of tetracycline in groundwater by nanoscale zero-valent iron-copper bimetallic biochar: active [H] attack and direct electron transfer mechanism.

Development of carbon materials with high activity was important for rapid degradation of emerging pollutants. In this paper, a novel nanoscale zero-valent iron-copper bimetallic biochar (nZVIC-BC) was synthesized by carbothermal reduction of waste pine wood and copper-iron layered double hydroxides (LDHs). Characterization and analysis of its structural, elemental, crystalline, and compositional aspects using XRD, FT-IR, SEM, and TEM confirmed the successful preparation of nZVIC-BC and the high dispersion of Fe-Cu nanoparticles in an ordered carbon matrix. The experimental results showed that the catalytic activity of nZVIC-BC (Kobs of 0.0219 min-1) in the degradation of tetracycline (TC) in anoxic water environment was much higher than that of Fe-BC and Cu-BC; the effective degradation rate reached 85%. It was worth noting that the negative effects of Ca2+, Mg2+, and H2PO4- on TC degradation at ionic strengths greater than 15 mg/L were due to competition for active sites. Good stability and reusability were demonstrated in five consecutive cycle tests for low leaching of iron and copper. Combined with free radical quenching experiments and XPS analyses, the degradation of TC under air conditions was only 62%, with hydroxyl radicals (·OH) playing a dominant role. The synergistic interaction between Fe2+/Fe3+ and Cu0/Cu+/Cu2+ under nitrogen atmosphere enhances the redox cycling process; π-π adsorption, electron transfer processes, and active [H] were crucial for the degradation of TC; and possible degradation pathways of TC were deduced by LC-MS, which identified seven major aromatic degradation by-products. This study will provide new ideas and materials for the treatment of TC.

Autophagy: A potential target for natural products in the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the mucosa of the colon and rectum. UC is characterized by recurrent episodes, often necessitating lifelong medication use, imposing a significant burden on patients. Current conventional and advanced treatments for UC have the disadvantages of insufficient efficiency, susceptibility to drug resistance, and notable adverse effects. Therefore, developing effective and safe drugs has become an urgent need. Autophagy is an intracellular degradation process that plays an important role in intestinal homeostasis. Emerging evidence suggests that aberrant autophagy is involved in the development of UC, and modulating autophagy can effectively alleviate experimental colitis. A growing number of studies have established that autophagy can interplay with endoplasmic reticulum stress, gut microbiota, apoptosis, and the NLRP3 inflammasome, all of which contribute to the pathogenesis of UC. In addition, a variety of intestinal epithelial cells, including absorptive cells, goblet cells, and Paneth cells, as well as other cell types like neutrophils, antigen-presenting cells, and stem cells in the gut, mediate the development of UC through autophagy. To date, many studies have found that natural products hold the potential to exert therapeutic effects on UC by regulating autophagy. This review focuses on the possible effects and pharmacological mechanisms of natural products to alleviate UC with autophagy as a potential target in recent years, aiming to provide a basis for new drug development.

Coagulation and fibrinolytic markers offer utility when distinguishing between benign and malignant gallbladder tumors: A cross-sectional study.

BACKGROUND: The metabolic or proliferative abnormalities that are characteristic of tumor cells can lead to abnormal fibrinolysis or coagulation system activity, with certain tumors exhibiting hypercoagulability or existing in a fibrinolytic state. However, the utility of biomarkers of coagulation and fibrinolysis when seeking to differentiate between benign gallbladder disease and malignant gallbladder tumors remains uncertain. METHODS: This study included a total of 81 patients with benign gallbladder polyps and 94 patients with malignant gallbladder tumors. Pre-biopsy or pretreatment levels of PT, APTT, FIB, D-dimer, FDP, PLT, PIC, TAT, TM, and t-PAIC from these patients were compared using Mann-Whitney tests. The baseline data of the patients were analyzed using chi-square tests, and the diagnostic utility of these biomarkers in distinguishing between benign and malignant gallbladder lesions was evaluated using ROC curves, and Spearman correlation analysis was employed to assess the correlation between these indicators and tumor parameters. RESULTS: The average age of malignant gallbladder tumor group was higher than benign gallbladder polyp group. And the base line analysis showed that there was a statistic difference in age, history of smoking, drinking, biliary tract disease, BMI of over weight between these two groups. In patients with malignant gallbladder tumors, FIB, D-dimer, FDP, PIC, TAT, TM, and t-PAIC levels were significantly elevated relative to those in patients affected by benign gallbladder polyp. The AUC for FIB, D-dimer, and FDP was 0.8469, 0.6514, 0.5950, while for PIC, TAT, TM, t-PAIC and four biomarker combined diagnosed was 0.8455, 0.6554, 0.7130, 0.6806, and 0.8859. Among these, TM was associated with the vascular invasion of tumor patients; TAT and t-PAIC were associated with neural invasion; D-dimer and FDP were related to the maximum tumor diameter; and FDP had a certain correlation with the tumor stage. CONCLUSIONS: In gallbladder tumor patients, conventional coagulation metrics like FIB, D-dimer, and FDP, as well as newer thrombotic indicators such as PIC, TAT, TM, and t-PAIC, were obviously increased. Correlations with tumor parameters suggested their potential as biomarkers to distinguish benign from malignant gallbladder growths.

Changing epidemiology of inflammatory bowel disease in children and adolescents.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) is rising worldwide, but epidemiological data on children and adolescents are lacking. Understanding the global burden of IBD among children and adolescents is essential for global standardization of methodology and treatment options. METHODS: This is a cross-sectional study based on aggregated data. We estimated the prevalence and incidence of IBD in children and adolescents between 1990 and 2019 according to the Global Burden of Disease Study 2019 (GBD 2019). Age-standardized rates (ASRs) and estimated annual percentage changes (EAPCs) were used to compare the burden and trends between different regions and countries. RESULTS: In 2019, there were 25,659 new cases and 88,829 prevalent cases of IBD among children and adolescents globally, representing an increase of 22.8% and 18.5%, respectively, compared to 1990. Over the past 30 years, the incidence and prevalence of IBD among children and adolescents have been highest in high SDI regions, with the most significant increases in East Asia and high-income Asia Pacific. At the age level, incidence and prevalence were significantly higher in the 15-19-year-old age group, while the < 5-year-old group showed the most significant increase in incidence and prevalence. CONCLUSION: The incidence of IBD in children and adolescents is significantly on the rise in some countries and regions, and IBD will remain an important public health issue with extensive healthcare and economic costs in the future. The reported IBD burden in children and adolescents at the global, regional, and national levels will assist in the development of more precise health policies.

Pollen-expressed RLCKs control pollen tube burst.

In angiosperms, the pollen tube enters the receptive synergid cell, where it ruptures to release its cytoplasm along with two sperm cells. This interaction is complex, and the exact signal transducers that trigger the bursting of pollen tubes are not well understood. In this study, we identify three homologous receptor-like cytoplasmic kinases (RLCKs) expressed in pollen tubes of Arabidopsis, Delayed Burst 1/2/3 (DEB1/2/3), which play a crucial role in this process. These genes produce proteins localized on the plasma membrane, and their knockout causes delayed pollen tube burst and entrance of additional pollen tubes into the embryo sac due to fertilization recovery. We show that DEBs interact with the Ca2+ pump ACA9, influencing the dynamics of cytoplasmic Ca2+ in pollen tubes through phosphorylation. These results highlight the importance of DEBs as key signal transducers and the critical function of the DEB-ACA9 axis in timely pollen tube burst in synergids.

Ferroptosis in ulcerative colitis: Potential mechanisms and promising therapeutic targets.

Ulcerative colitis (UC) is a complex immune-mediated chronic inflammatory bowel disease. It is mainly characterized by diffuse inflammation of the colonic and rectal mucosa with barrier function impairment. Identifying new biomarkers for the development of more effective UC therapies remains a pressing task for current research. Ferroptosis is a newly identified form of regulated cell death characterized by iron-dependent lipid peroxidation. As research deepens, ferroptosis has been demonstrated to be involved in the pathological processes of numerous diseases. A growing body of evidence suggests that the pathogenesis of UC is associated with ferroptosis, and the regulation of ferroptosis provides new opportunities for UC treatment. However, the specific mechanisms by which ferroptosis participates in the development of UC remain to be more fully and thoroughly investigated. Therefore, in this review, we focus on the research advances in the mechanism of ferroptosis in recent years and describe the potential role of ferroptosis in the pathogenesis of UC. In addition, we explore the underlying role of the crosslinked pathway between ferroptosis and other mechanisms such as macrophages, neutrophils, autophagy, endoplasmic reticulum stress, and gut microbiota in UC. Finally, we also summarize the potential compounds that may act as ferroptosis inhibitors in UC in the future.

From gut to brain: understanding the role of microbiota in inflammatory bowel disease.

With the proposal of the "biological-psychological-social" model, clinical decision-makers and researchers have paid more attention to the bidirectional interactive effects between psychological factors and diseases. The brain-gut-microbiota axis, as an important pathway for communication between the brain and the gut, plays an important role in the occurrence and development of inflammatory bowel disease. This article reviews the mechanism by which psychological disorders mediate inflammatory bowel disease by affecting the brain-gut-microbiota axis. Research progress on inflammatory bowel disease causing "comorbidities of mind and body" through the microbiota-gut-brain axis is also described. In addition, to meet the needs of individualized treatment, this article describes some nontraditional and easily overlooked treatment strategies that have led to new ideas for "psychosomatic treatment".

Distribution, migration patterns, and food chain human health risks of endocrine-disrupting chemicals in water, sediments, and fish in the Xiangjiang River.

Exposure to endocrine-disrupting chemicals (EDCs) in freshwater systems has garnered increasing attention. A comprehensive analysis of the migration patterns, bioaccumulation, and consumer health risk of EDCs along the Xiangjiang River due to fish consumption from the river ecosystem was provided. Twenty natural and synthetic target EDCs were detected and analyzed from the water, sediments, and fish samples collected along the Xiangjiang River. There were significant correlations between the EDC concentrations in fish and the sediments. This revealed that EDCs in sediments play a dominant role in the uptake of EDCs by fish. The bioaccumulation factor and biota-sediment accumulation factor were calculated, with the highest values observed for nonylphenol. Pearson's correlation analysis showed that bisphenol A is the most reliable biological indicator of EDC contamination in fish. Furthermore, based on the threshold of toxicological concerns and the health risk with dietary intake, crucian carp and catfish from the Xiangjiang River pose a certain risk for children and pregnant women compared to grass carp. The Monte Carlo simulation results indicated a certain risk of cumulative ∑EDC exposure for local residents due to fish consumption.

Childhood Gender Nonconformity and Sexual Orientation Disparities in Depressive Symptoms: The Role of Parental Attitudes.

Purpose: This study tested whether sexual orientation disparities in depressive symptoms are partially explained by recalled childhood gender nonconformity and whether the proportion of this association explained by childhood gender nonconformity is moderated by recalled parental attitudes toward childhood gender nonconformity. Methods: A convenience sample of young adults was recruited from two Chinese online survey platforms (272 heterosexual males, 272 bisexual males, 272 gay males, 272 heterosexual females, 272 bisexual females, and 272 lesbian females). Both mediation and moderated mediation models were conducted. Results: For both sexes, bisexual and gay/lesbian individuals reported significantly higher levels of depressive symptoms than heterosexual individuals, with total effects (standardized path coefficients) ranging from 0.25 to 0.38, all ps < 0.01. These sexual orientation disparities in depressive symptoms were partially explained by childhood gender nonconformity, with indirect effects ranging from 0.08 to 0.17, all ps < 0.001. The effect of childhood gender nonconformity on depressive symptoms was significantly moderated by parental attitudes. The mediating effect of childhood gender nonconformity on sexual orientation disparities in depressive symptoms was strongest at the more negative levels (one standard deviation [SD] above the mean) of parental attitudes and weakest at more tolerant levels (one SD below the mean) of parental attitudes. Conclusions: Childhood gender nonconformity may be a partial contributor to sexual orientation disparities in depressive symptoms and this indirect effect may be moderated by parental attitudes toward childhood gender nonconformity, with the indirect effect decreasing when parental attitudes move from negative toward more tolerant levels.

Ultra-compact, low-loss,TE0- and TE1-compatible mode waveguide bends.

Waveguide bends have become an interesting research direction because they allow highly curved light transmission in a limited space. Here, we propose waveguide bends supporting two TE modes by etching slots and adding germanium arcs in the inner side of a waveguide bend. Simulations show that the bending radius of our proposed base-mode T E 0 waveguide bend drops to 500 nm and its insertion loss (IL) is reduced to 0.13 dB with footprints as small as 0.75µm×0.75µm. For the higher-order T E 1 mode waveguide bend, we adjust the introduced structure in combination with the light field distribution. The IL of the waveguide bend is also reduced to 0.18 dB with footprints as small as 1.85µm×1.85µm. T E 0 mode has 410 nm bandwidth in the optical communication band while T E 1 mode has 330 nm bandwidth by keeping I L<0.5d B. Through the analysis of these structural characteristics, we believe that this method still has great potential in higher-order mode transmission.

Boosting Efficient Alkaline Hydrogen Evolution Reaction of CoFe-Layered Double Hydroxides Nanosheets via Co-Coordination Mechanism of W-Doping and Oxygen Defect Engineering.

While surface defects and heteroatom doping exhibit promising potential in augmenting the electrocatalytic hydrogen evolution reaction (HER), their performance remains unable to rival that of the costly Pt-based catalysts. Yet, the concurrent modification of catalysts by integrating both approaches stands as a promising strategy to effectively address the aforementioned limitation. In this work, tungsten dopants are introduced into self-supported CoFe-layered double hydroxides (LDH) on nickel foam using a hydrothermal method, and oxygen vacancies (Ov) are further introduced through calcination. The analysis results demonstrated that tungsten doping reduces the Ov formation energy of CoFeW-LDH. The Ov acted as oxophilic sites, facilitating water adsorption and dissociation, and reducing the barrier for cleaving HO─H bonds from 0.64 to 0.14 eV. Additionally, Ov regulated the electronic structure of CoFeW-LDH to endow optimized hydrogen binding ability on tungsten atoms, thereby accelerating alkaline Volmer and Heyrovsky reaction kinetics. Specifically, the abundance of Ov induced a transition of tungsten from a six-coordinated to highly active four-coordinated structure, which becomes the active site for HER. Consequently, an ultra-low overpotential of 41 mV at 10 mA cm-2 , and a low Tafel slope of 35 mV dec-1 are achieved. These findings offer crucial insights for the design of efficient HER electrocatalysts.

Diet-derived circulating antioxidants and risk of inflammatory bowel disease: a Mendelian randomization study and meta-analysis.

Background: Previous studies have shown conflicting results regarding the impact of circulating antioxidants on the risk of inflammatory bowel disease (IBD). In this study, our intent was to investigate the causal relationship between circulating antioxidants and IBD using Mendelian randomization (MR). Methods: Instrumental variables for absolute circulating antioxidants (ascorbate, retinol, lycopene, and ß-carotene) and circulating antioxidant metabolites (α-tocopherol, γ-tocopherol, ascorbate, and retinol) were screened from published studies. We obtained outcome data from two genome-wide association study (GWAS) databases, including the international inflammatory bowel disease genetics consortium (IIBDGC, 14,927 controls and 5,956 cases for Crohn's disease (CD), 20,464 controls and 6,968 cases for ulcerative colitis (UC), and 21,770 controls and 12,882 cases for IBD) and the FinnGen study (375,445 controls and 1,665 cases for CD, 371,530 controls and 5,034 cases for UC, and 369,652 controls and 7,625 cases for IBD). MR analysis was performed in each of the two databases and those results were pooled using meta-analysis to assess the overall effect of exposure on each phenotype. In order to confirm the strength of the findings, we additionally conducted a replication analysis using the UK Biobank. Results: In the meta-analysis of the IIBDGC and FinnGen, we found that each unit increase in absolute circulating level of retinol was associated with a 72% reduction in the risk of UC (OR: 0.28, 95% CI: 0.10 to 0.78, P=0.015). The UC GWAS data from the UK Biobank also confirmed this causal relationship (OR: 0.99, 95% CI: 0.97 to 1.00, P=0.016). In addition, there was suggestive evidence that absolute retinol level was negatively associated with IBD (OR: 0.41, 95% CI: 0.18 to 0.92, P=0.031). No other causal relationship was found. Conclusion: Our results provide strong evidence that the absolute circulating level of retinol is associated with a reduction in the risk of UC. Further MR studies with more instrumental variables on circulating antioxidants, especially absolute circulating antioxidants, are needed to confirm our results.

Childhood Gender Nonconformity and Parental Maltreatment as Mediators of Sexual Orientation Disparities in Childhood Emotional and Behavioral Difficulties.

The mechanisms underlying sexual orientation differences in psychopathology originating in childhood remain understudied since sexual orientation does not directly manifest in childhood. This study tested whether childhood gender nonconformity and parental maltreatment before age 6 years 9 months partly explained sexual orientation disparities in the developmental trajectories of emotional and behavioral difficulties from age 6 years 9 months to 11 years 8 months. The Avon Longitudinal Study of Parents and Children was used (2182 boys and 2422 girls, Mage = 15.5, 90% White). After controlling for early life factors, non-heterosexual boys and girls displayed significantly greater emotional and behavioral difficulties than their heterosexual counterparts at all three ages. There was a sex difference in the mediating effects. For girls, sexual orientation disparities in childhood emotional and behavioral difficulties were partially explained by childhood gender nonconformity. For boys, sexual orientation disparities in childhood emotional and behavioral difficulties were partially explained by a path through greater childhood gender nonconformity, leading to increased risk of being the targets of parental maltreatment. Childhood gender nonconformity, parental maltreatment, and other early life factors only partially explain sexual orientation disparities in childhood emotional and behavioral difficulties. The mediating effects of childhood gender nonconformity and parental maltreatment on the association between sexual orientation and childhood emotional and behavioral difficulties differ between the sexes.

Research progress on influencing factors affecting the efficacy of moxibustion in treating knee osteoarthritis. / è‰¾ç¸æ²»ç–—è†å ³èŠ‚éª¨å ³èŠ‚ç‚Žçš„ç–—æ•ˆå½±å“å› ç´ ç ”ç©¶è¿›å±•.

The article summarizes the relevant factors to the therapeutic effect of moxibustion on knee osteoarthritis, including the origin and storage time of moxa leaves, the time of moxibustion, the numbers of moxa cone, and the temperature when moxibustion is operated. Artemisia mugwort in Qichun county stored for over 3 years is the best regarding its property； and it is recommended for about 40 min in suspended moxibustion； and the heat-sensitive moxibustion is determined when the sensation of moxibustion disappears； and in terms of moxibustion techniques and the numbers of moxa cone, two moxa cones are optimal in warm needling, but the highly applicable duration of moxibustion needs to be confirmed through more high-quality studies. There are few studies on the other influencing factors, such as the specific operation of suspended moxibustion, the angle of knee flexion, treatment sequence, light and smoking factors, moxibustion method and disease staging and type； and the studies are limited in the comparison in terms of the middle-term and long-term efficacy, the comparison of the efficacy among different syndromes of traditional Chinese medicine in patients and the comparison among various frequencies and sessions of treatment. In future, more high-quality clinical trials should be designed to complete the evidence-based regimens and optimize clinical operations.

Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model.

BACKGROUND: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options. Recombinant adeno-associated virus (rAAV) provides a promising platform for gene therapy on such kinds of diseases. A microRNA (miRNA) let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated. AIM: To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8 (rAAV8) on a xenobiotic-induced mouse model of sclerosing cholangitis. METHODS: A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) feeding for 2 wk or 6 wk. A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding. Upon sacrifice, the liver and the serum were collected from each mouse. The hepatobiliary injuries, hepatic inflammation and fibrosis were evaluated. The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot. RESULTS: rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk. The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers, and prevent the proliferation of cholangiocytes and biliary fibrosis. Furthermore, inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1, which consequently inhibit of NF-κB-mediated hepatic inflammation. CONCLUSION: Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis, which provides a possible clinical translation of PSC of human.

Novel prognostic marker TGFBI affects the migration and invasion function of ovarian cancer cells and activates the integrin αvß3-PI3K-Akt signaling pathway.

BACKGROUND: Individual patients with ovarian cancer show remarkably different prognosis. Present prognostic models for ovarian cancer mainly focus on clinico-pathological parameters, so quantifiable prognostic markers at molecular level are urgently needed. Platelets contribute to ovarian cancer progression, but have not been considered as biomarkers likely due to their instability. Here, we aimed to search for a stable prognostic marker from platelet-treated ovarian cancer cells, and explore its functions and mechanisms. METHODS: Microarrays analysis was done with platelet-treated SKOV-3 ovarian cancer cells. Relevant studies were searched in the Gene Expression Omnibus (GEO) database. The candidate genes were determined by differentially expressed genes (DEGs), Venn diagram drawing, protein-protein interaction (PPI) network, Cox proportional hazards model and Kaplan-Meier analysis. The expression of TGFBI in clinical samples was assessed by immunehistochemical staining (IHC), and the association of TGFBI levels with the clinic-pathological characteristics and prognosis in ovarian cancer patients was evaluated by univariate and multivariate analysis. The functions of TGFBI were predicted using data from TCGA, and validated by in vitro and in vivo experiments. The mechanism exploration was performed based on proteomic analysis, molecular docking and intervention study. RESULTS: TGFBI was significantly higher expressed in the platelet-treated ovarian cancer cells. An analysis of bioinformatics data revealed that increased expression of TGFBI led to significant decrease of overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS) in ovarian cancer patients. Tissue microarray results showed that TGFBI was an independent factor for ovarian cancer, and TGFBI expression predict poor prognosis. Functionally, TGFBI affected the migration and invasion of ovarian cancer cells by regulation of epithelial mesenchymal transition (EMT) markers (CDH1 and CDH2) and extracellular matrix (ECM) degradation proteins (MMP-2). Mechanistically, TGFBI phosphorylated PI3K and Akt by combining integrin αvß3. CONCLUSIONS: We found out TGFBI as a novel prognostic indicator for ovarian cancer patients. TGFBI could promote metastasis in ovarian cancer by EMT induction and ECM remodeling, which might be associated with the activation of integrin αvß3-PI3K-Akt signaling pathway.

Ultrabright Green-Emissive Nanodots for Precise Biological Visualization.

Developing general methods to fabricate water-dispersible and biocompatible fluorescent probes will promote different biological visualization applications. Herein, we report a metal-facilitated method to fabricate ultrabright green-emissive nanodots via the one-step solvothermal treatment of rose bengal, ethanol, and various metal ions. These metal-doped nanodots show good water dispersity, ultrahigh photoluminescence quantum yields (PLQYs) (e.g., the PLQY of Fe-doped nanodots (FeNDs) was ∼97%), and low phototoxicity. Owing to the coordination effect of metal ions, the FeNDs realize glutathione detection with outstanding properties. Benefiting from the high endoplasmic reticulum (ER) affinity of the chloride group, the FeNDs can act as an ER tracker with long ER imaging capacity (FeNDs: >24 h; commercial ER tracker: ∼1 h) and superb photostability and can achieve tissue visualization in living Caenorhabditis elegans. The metal-doped nanodots represent a general nanodot preparation method and may shed new light on diverse biological visualization uses.